Many conditions in humans and animals are caused by fungal infections and current therapeutics for the prevention of and treatments for these infections are largely ineffective. Coccidioidomycosis, also known as San Joaquin Valley Fever, is a fungal disease caused by Coccidioides immitis that is endemic in portions of Southern Arizona, central California, southern New Mexico and west Texas. At least 100,000 new cases are reported each year. The migration of not only permanent residents, but also agricultural workers to these areas increases exposure to C. immitis spores that lie dormant in the soil, and as the soil is disturbed, the spores become airborne and are inhaled. Once in the lungs, the arthroconidia transform into spherules. An acute respiratory infection occurs between seven days to three weeks after exposure and often resolves rapidly. However, in a significant number of cases, chronic pulmonary conditions or dissemination to the meninges, bones, and joints can result, leading to acute, life-threatening disease. One population, migrant laborers, is exposed to C. immitis and are a highly susceptible to get infected. A variety of approaches have been used to fight coccidioidomycosis, including soil treatments, but only a vaccine can completely eliminate this “emerging disease.”
Another pathogen, Cryptococcus neoformans is an encapsulated pathogenic yeast that causes pulmonary infections and meningoencephalitis in humans and other animals. During the last 20 years, there has been a dramatic increase in the incidence of cryptococcosis throughout the world that mirrors the increase in not only HIV infections, but also in the growing number of immunocompromised patients. Loss of CD4+ T cells predisposes patients to progressive infection with C. neoformans—this emphasizes the role of cell-mediated immunity in host resistance.
C. neoformans is a basidiomycetous fungus that is generally isolated as a haploid yeast, although diploids have been identified in nature. There are two mating types that can undergo recognition and fusion, and form a mycelium. A structure called a basidium is made and spores are produced from the surface of the basidium. Under specific conditions, haploid cells can undergo sporulation. Recently, a stable diploid was shown to grow as a yeast at 37° C. and formed hyphae and produced spores at 24° C. C. neoformans has been the subject of many studies, the var. grubii strain H99, as the source of the candidate immunogens. Var. grubii are serotype A strains, have a worldwide distribution, and are the most common variety to cause disease in the United States. Strain H99 has several advantages. First, molecular genetic analysis, including gene deletion and allelic replacement experiments, are well established in H99. Second, the genome sequence of H99 has been determined. The random shotgun and assembly phases of the genome are complete and the assembled genome has been released. Third, a congenic mating partner for H99 has recently been developed. Lastly, several reproducible animal models have been well developed to assess virulence for this strain.
Cryptococcosis is a disease that is acquired by inhalation of the organism from the soil or avian droppings into the lungs. Both immunocompetent and immunocompromised patients can be infected with the organism. In immunocompetent patients, the disease is usually contained in a lung granuloma and induces an antibody response. In contrast, individuals whose cellular immunity has been compromised by viral infection, suppression due to tissue transplantation, or anti-neoplastic chemotherapy are particularly susceptible to disseminated disease, followed by often-fatal meningoencephalitis. For example, an estimated 7-10% of AIDS patients acquire cryptococcosis during the course of their HIV disease. In compromised hosts, patients with cryptococcosis generally present with symptoms of meningitis such as fever, headache, and malaise. Cryptococcal pneumonia is the next most frequent manifestation of cryptococcosis in immunocompromised patients. It occurs as a primary infection in approximately 4% of cases and is associated with general symptoms of pneumonia such as fever, cough, pleuritic chest pain, and/or dyspnea.
Aspergillus fumigatus is a ubiquitous spore-bearing fungus that causes multiple diseases in humans. These include allergic asthma, aspergillomas, and invasive pulmonary disease of hosts with predisposing underlying conditions. In the United States in 1996, there were an estimated 10,190 aspergillosis-related hospitalizations; these resulted in 1,970 deaths, 176,300 hospital days, and $633 million in costs. The average hospitalization lasted 17.3 days and cost ˜$62,000. Although aspergillosis-related hospitalizations account for a small percentage of hospitalizations in the United States, patients hospitalized with the condition have lengthy hospital stays and high mortality rates. The high mortality rates (in some instances over 90%) are due, in part, to the lack of rapid and sensitive diagnostic tests (all too often the diagnosis is made post mortem), as well as the lack of effective anti-fungal therapeutics.
The most common species of Aspergillus causing invasive disease include A. fumigatus, A. flavus, A. niger, A. terreus and A. nidulans. A. fumigatus is the most frequently found fungus in airborne spore surveys. The organism grows in a variety of environments including air ducts, houseplant soil, compost piles, and at a wide range of temperatures, from ˜12° C. to 55° C. Of the genus Aspergillus, A. fumigatus is the most common pathogen of man.
Currently, there are a number of anti-fungal vaccine and anti-fungal treatment effort that use a variety of approaches including selected recombinantly-expressed antigens. Safe and effective vaccines against fungal organisms as well as against other similar pathogens are needed.